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Mechanism of DNA binding by the ALT-essential factor FANCM
FANCM is a tumour-suppressive DNA translocase that resolves replication stress through its N-terminal translocase domain, which couples branched DNA binding with ATP hydrolysis to perform ‘branch migration’. This activity is necessary for both tumour-suppression and for the survival of cancer cells which utilise the Alternative Lengthening of Telomeres (ALT) mechanism.
We used a combination of biochemical, biophysical, and structural biology techniques to examine the N-terminal translocase domain of FANCM. We show that the Hel2i and ‘mincer’ subdomain within the translocase are critical for branched DNA substrate engagement, and for the coupling of ATPase and branch migration activity, respectively. Mutation of DNA-interacting residues within the ‘mincer’ domain uncouples ATP hydrolysis from branch migration, while loss of Hel2i, or mutation of crucial DNA-binding residues within Hel2i, disrupts the ability of FANCM to functionally engage its substrate and abrogates its branch migration activity. Furthermore, FANCM Hel2i mutants also fail to rescue telomeric replication stress, highlighting the importance of branched DNA binding by FANCM for ALT-positive cancer cell survival.
Our results demonstrate how FANCM couples branched DNA binding to ATPase activity, necessary for resolving replication stress, and provide novel insight into the mechanism of tumour suppression by FANCM.
Date:
22 May 2025, 14:00
Venue:
Medical Sciences Teaching Centre, off South Parks Road OX1 3PL
Venue Details:
Room 3 a/b
Speaker:
Dr Lara Abbouche (St Vincents Institute, Melbourne)
Organising department:
Sir William Dunn School of Pathology
Organiser:
Melissa Wright (Sir William Dunn School of Pathology)
Organiser contact email address:
melissa.wright@path.ox.ac.uk
Hosts:
Dr Rebecca Smith (Sir William Dunn School of Pathology),
Prof Ivan Ahel (Dunn School of Pathology)
Part of:
Dunn School of Pathology Research Seminars
Booking required?:
Not required
Audience:
Members of the University only
Editor:
Melissa Wright
